Breast cancer is the most common female malignancy in most industrialized countries, as it is estimated to affect about 10% of the female population during their lifespan. Although its mortality has not increased along with its incidence, due to earlier diagnosis and improved treatment, it is still one of the predominant causes of death in middle-aged women.
The primary treatment for breast cancer is surgery, either alone or combined with systemic adjuvant therapy (hormonal or cytotoxic) and/or post-operative irradiation. Most patients are cured with these treatments, but approximately 25-30% of women with node-negative disease and at least 50-60% of women with positive nodes, who appear to be disease-free after locoregional treatment, will relapse and need treatment for their metastatic disease. Thus, metastatic breast cancer is a significant and growing problem in oncology.
Approximately 30 to 40% of women with operable breast cancer eventually develop distant metastases. Metastatic breast cancer is commonly treated with anthracyclines, such as doxorubicin and epirubicin, which act via inhibiting the topoisomerase II (TOP2A) enzyme in cancer cells. A favorable response to TOP2A inhibitor-based chemotherapy improves post-chemotherapy survival and has a positive effect on the quality of life.
The response of patients to topoisomerase II inhibitors is widely variable. In addition, only 5 to 10% of breast cancer patients with overtly metastatic disease achieve complete clinical remission. In 30 to 50% of such cases, the response is partial, and the duration of response typically ranges from 6 to 24 months. In the remaining patients, either no objective response is detected, or the disease progresses despite ongoing treatment.
Overexpression of the HER-2 receptor protein (ERBB2) has long been associated with more aggressive breast cancer and results primarily from amplification of the gene HER-2/neu, also referred to as ERBB2 or more simply as HER-2. More importantly, HER-2 amplification is an established predictor of tumor response to the humanized anti-ERBB2 antibody trastuzumab (sold commercially as Herceptin® by Genentech). However, breast carcinomas lacking HER-2 amplification rarely respond to trastuzumab while 20-40% of tumors with HER-2 amplification have good response. Moreover, trastuzumab has cardiotoxic side effects and is expensive. Thus, there is a need for methods for identifying those tumors that can be treated more successfully with trastuzumab. Such methods will enable physicians to better match trastuzumab therapy with patients more likely to benefit from such therapy, thereby avoiding prescription of trastuzumab therapy for patients unlikely to benefit from trastuzumab and further avoiding the attendant patient morbidity and cost of doing so.
It has been suggested that candidates for effective treatment with TOP2A inhibitors can be identified by detecting the copy numbers for HER-2/neu and TOP2A. U.S. 2003/0134279A1 by Isola, et al. Patients indicating amplification of both HER-2/neu and TOP2A are said to be good candidates for treatment with TOP2A inhibitors.